The adenomatous polyposis coli (APC) gene is a tumor suppressor gene identified as a causative gene of Familial Adenomatous Polyposis (FAP). It has been shown that mutation of the APC gene is not restricted to FAP, but is involved also in the development of non-hereditary adenomatous polyposis and colon cancer (Polakis, P., Biochim Biophys Acta. (1997) 1332, F127-147). In FAP patients, many benign polyps form in the colon, from which malignantly transformed cancer cells develop. Although colon cancer develops through multistep changes that occur in a great number of oncogenes and tumor suppressor genes, mutations in the APC gene are found at the earliest stage. Therefore, APC gene abnormalities are considered to be causes of colon cancer.
The APC protein (hereinafter, APC) is a large protein having a molecular weight of approximately 310 kDa comprising 2843 amino acids, and binds to a great number of proteins. To date, it has been reported to bind directly to the B56 subunit of PP2A phosphatase; APC-stimulated guanine nucleotide exchange factor (Asef); KAP3/KIF3A/KIF3B microtubule-associated motor protein complex belonging to the kinesin family; β-catenin/GSK-3β/Axin, a constituent of the Wnt signal transduction pathway; microtubules, which are cytoskeleton components; proteins of the microtubule-associated protein EB/RP family; p34cdc2 kinase, a cell cycle regulatory factor; Siah-1, an apoptosis-related protein; and hDLG, a tumor suppressor gene product (for a review, see Bienz, M., Nat. Rev. Mol. Cell Biol. (2002) 3(5), 328-338). In the polyps and colon cancer cells of FAP patients, mutations occur in both of the APC alleles, and only mutant APCs that have lost their C-terminal regions due to a truncation in the middle are expressed. Cells are thought to become cancerous because such mutant APCs exhibit abnormal functions.
APC has been reported to promote β-catenin degradation by complexing with β-catenin/GSK-3β/Axin, and to function in maintaining a low level of existing β-catenin (Rubinfeld, B., Science (1993) 262:1731-1734; Su, L. K., Science (1993) 262:1734-1737). When β-catenin is present in large amounts, it is transferred into the nucleus where it binds to a transcription factor and promotes cell proliferation. Therefore, initially, APC was considered to function as a tumor suppressor protein by regulating the level of existing β-catenin. However, detailed observation of the polyp-forming process using FAP model mice showed that epithelial cells which had differentiated in the crypt region could not migrate normally to the villus apex, and therefore dropped into the inside of the villus at the crypt-villus boundary, becoming morphologically different from their original form, resulting in polyps (Oshima, M., et al., Cancer Res. (1997 57 (9), 1644-1649). Furthermore, promotion of cell proliferation does not take place inside the polyps, and epithelial cells that develop morphologies different from the original state while maintaining an intercellular adhesive structure were proved to be the cause of polyp formation. Therefore, APC is now considered to be involved in regulating cell morphology and motility. Furthermore, APC was found to bind to Asef, which functions in the regulation of the actin cytoskeleton (Kawaki, Y., et. al. Science (2000) 289(5482), 1194-1197), and to microtubules at the leading edges of motile cells (Mimori-Kiyosue, Y. et. al., J. Cell Biol. (2000) 148(3), 505-518). The possibility of APC involvement in cytoskeleton regulation is beginning to be considered.
Elucidation of the functions of normal and mutant APCs in cell morphology and motility, and elucidation of the causes of polyp formation and malignant transformation have long been anticipated.